The goal of this Program Project Grant (PPG) is to develop innovative immunotherapies for the treatment or prevention of the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). The first project studies the use of gene therapy to treat EAE. This project centers on delivery of regulatory proteins (cytokines and blockade of TNFalpha) to lesions of EAE. The second project tests another model of gene therapy using retroviral delivery of protein inhibitors to interfere with the function of NFAT and NFkappaB. The goals of the second project interrelate with those of the first project through the attempt to target the autoimmune T cells in lesions of EAE as potential targets of immune intervention. The third project proposed DNA vaccination as a potential immunotherapy of EAE. This project will assess the development of and regulatory effects of DNA vaccination on the development of immune response to various cell surface molecules involved in the inflammatory cascade in EAE. We believe these three projects provide an integrated attempt to explore fundamental issues in the development of immunotherapy of EAE. Insights gained from these studies may have enormous application to the future treatment of several different autoimmune diseases. Importantly, the three investigators have worked together developing the expertise and rationale for this proposal. The combined effort of these three investigators should provide the model of a successful PPG.